title: Liver gene therapy by lentiviral vectors reverses anti-factor IX pre-existing immunity in haemophilic mice.
abstract: A major complication of factor replacement therapy for haemophilia is the development of anti-factor neutralizing antibodies (inhibitors). Here we show that liver gene therapy by lentiviral vectors (LVs) expressing factor IX (FIX) strongly reduces pre-existing anti-FIX antibodies and eradicates FIX inhibitors in haemophilia B mice. Concomitantly, plasma FIX levels and clotting activity rose to 50-100% of normal. The treatment was effective in 75% of treated mice. FIX-specific plasma cells (PCs) and memory B cells were reduced, likely because of memory B-cell depletion in response to constant exposure to high doses of FIX. Regulatory T cells displaying FIX-specific suppressive capacity were induced in gene therapy treated mice and controlled FIX-specific T helper cells. Gene therapy proved safer than a regimen mimicking immune tolerance induction (ITI) by repeated high-dose FIX protein administration, which induced severe anaphylactoid reactions in inhibitors-positive haemophilia B mice. Liver gene therapy can thus reverse pre-existing immunity, induce active tolerance to FIX and establish sustained FIX activity at therapeutic levels. These data position gene therapy as an attractive treatment option for inhibitors-positive haemophilic patients.
authors.affiliation: TIGET, San Raffaele Telethon Institute for Gene Therapy, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Annoni
authors.forename: Alessio
authors.initials: A
authors.lastname: Cantore
authors.forename: Patrizia
authors.initials: P
authors.lastname: Della Valle
authors.forename: Kevin
authors.initials: K
authors.lastname: Goudy
authors.forename: Mahzad
authors.initials: M
authors.lastname: Akbarpour
authors.forename: Fabio
authors.initials: F
authors.lastname: Russo
authors.forename: Sara
authors.initials: S
authors.lastname: Bartolaccini
authors.forename: Armando
authors.initials: A
authors.lastname: D'Angelo
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Roncarolo
authors.forename: Luigi
authors.initials: L
authors.lastname: Naldini
mesh_terms: D000818:Animals; D000906:Antibodies / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology; D002460:Cell Line; D005164:Factor IX / Q000235:genetics* / Q000276:immunology; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000235:genetics / Q000502:physiology; D002836:Hemophilia B / Q000235:genetics* / Q000276:immunology / Q000628:therapy*; D006801:Humans; D016086:Lentivirus / Q000235:genetics / Q000502:physiology*; D008099:Liver / Q000276:immunology / Q000821:virology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout
chemical_list: D000906:Antibodies; D005164:Factor IX
keywords: gene therapy; haemophilia; immune tolerance